Lung disease is the primary determinant of life expectancy and quality of life among people with the genetic disease cystic fibrosis (CF). The opportunistic Gram-negative bacterium Pseudomonas aeruginosa infects the respiratory tracts of most patients with CF, and infection with this pathogen is clearly associated with worse respiratory outcomes. P. aeruginosa infects CF airways early in life. Over many years, bacteria adapt to the CF airway environment and stimulate inflammatory responses that are ineffective in eradicating the infection, yet damage airways. The development of strategies to prevent P. aeruginosa colonization and eliminate chronic infection will require an understanding of the natural history of the bacterial contribution to CF lung disease. This proposal describes a four-year plan to further establish the independent, translational research career for the candidate. In particular, the candidate, a trained physician and microbiologist, will continue his clinical research training and focus his time on his funded, collaborative project to define the natural history of P. aeruginosa changes during early CF airway infection. This project uses the P. aeruginosa clinical isolates, linked clinical data, and unique clinical research mentorship opportunities available from two locally-led, national studies of CF microbiology, the Early Antipseudomonal Therapy in Cystic Fibrosis studies (EPIC). Specifically, this project will define the clinical relevance of infection with P. aeruginosa carrying a newly-identified adaptive change: inactivating mutation in the gene encoding the major transcriptional regulator LasR. This mutation was associated in our preliminary studies with accelerated lung function decline. Perhaps related to this finding, preliminary evidence suggests that LasR mutation leads to increased resistance to the antibiotics used most often in CF therapy. Conversely, LasR mutants are more susceptible in vitro to at least two classes of metabolic inhibitors, suggesting alternative therapeutic strategies for patients infected with these isolates. Thus, the emergence of LasR mutation during chronic P. aeruginosa CF airway infections may serve as a marker for advancing disease, and novel therapies could be developed for patients carrying these adaptive mutants. However, to address the utility of these approaches, our preliminary epidemiologic findings must be validated in a larger, multicenter population. We aim to define the prevalence and associated clinical features of LasR mutant P. aeruginosa infection among the young children enrolled in the EPIC trials, to test the hypothesis that LasR mutation occurs relatively commonly and early during P. aeruginosa CF infections, and is associated with preceding antibiotic exposure, accelerated decline in lung function, and more frequent respiratory exacerbations. Here, we also propose to compare results concerning LasR mutation with those for other common P. aeruginosa CF adaptive changes in this population. The results of this study will clarify the natural history of CF lung disease, and may lead to improvements in current CF therapeutic regimens.